We have demonstrated that inhibition of renin release by NaCl is specifically related to chloride and have hypothesized that renin release is inversely related to the magnitude of absorptive chloride transport in the thick ascending limb of the loop of Henle. The proposed studies are designed to evaluate this hypothesis. We will study the effect of three distinct pertubations of loop function (potassium depletion, adrenal insufficiency, and mannitol) on the chloride signal for renin release. We will determine if alterations of renin release induced by these perturbations are associated with alterations of solute transport in the loop of Henle, measured directly using micropuncture techniques. To evaluate the relationship between renin release and loop function in man, free water clearance (CH2O) will be used as an index of chloride transplant in the ascending limb of the loop. CH2O and plasma renin activity (PRA) will be measured in normal human subjects during infusion of hypotonic NaCl and hypotonic NaHCO3. An association between increased CH2Oand decreased PRA would be consistent with our hypothesis. In addition, to determine if the "defects" in low renin and high renin hypertension are related to alterations of chloride transport in the loop, we will determine if CH2O differs in patients with low renin, normal renin, and high renin essential hypertension. Finally, we proposed to apply our observations to the treatment of hypertension by determining if inhibition of renin release by selective chloride (without sodium) loading lowers arterial pressure in an experimental model of renin dependent hypertension.